Licata SC, Rowlett JK. Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond. Pharmacol Biochem Behav 90: 74-89

McLean Hospital/Harvard Medical School, Behavioral Psychopharmacology Research Laboratory, 115 Mill Street, Belmont, MA 02478, United States.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 08/2008; 90(1):74-89. DOI: 10.1016/j.pbb.2008.01.001
Source: PubMed


Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.

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Available from: James K Rowlett, Jan 03, 2014
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    • "Interestingly, so far benzodiazepines have not been shown to increase dopamine levels in the NAc as determined by dialysis, at least after acute administration . On the contrary, a number of studies showed a reduction in the extracellular dopamine concentrations in NAc following the systemic administration of benzodiazepines (Invernizzi et al, 1991; Finlay et al, 1992; Takada et al, 1993), a paradoxical finding considering the modest but well-documented reinforcing actions of benzodiazepines in humans and laboratory animals (see Licata and Rowlett (2008) for a review). This could indicate that benzodiazepines affect the mesolimbic dopamine system differently than other drugs of abuse, for example, by simultaneously modulating multiple sites in this circuit, and/or that benzodiazepines may exert their effects through routes that do not directly involve dopamine signaling. "
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    ABSTRACT: Despite long-standing concerns regarding the abuse liability of benzodiazepines, the mechanisms underlying properties of benzodiazepines that may be relevant to abuse are still poorly understood. Earlier studies showed that compounds selective for α1-containing GABAA receptors (α1GABAARs) are abused by humans and self-administered by animals, and that these receptors may underlie a preference for benzodiazepines as well as neuroplastic changes observed in the ventral tegmental area following benzodiazepine administration. There is some evidence, however, that even L-838, 417, a compound with antagonistic properties at α1GABAARs and agonistic properties at the other three benzodiazepine-sensitive GABAA receptor subtypes, is self-administered, and that the α2GABAARs may have a role in benzodiazepine-induced reward enhancement. Using a two-bottle choice drinking paradigm to evaluate midazolam preference and an intracranial self-stimulation (ICSS) paradigm to evaluate the impact of midazolam on reward enhancement, we demonstrated that mice carrying a histidine-to- arginine point mutation in the α2 subunit which renders it insensitive to benzodiazepines [α2(H101R) mice] did not prefer midazolam and did not show midazolam-induced reward enhancement in ICSS, in contrast to wild-type controls, suggesting that α2GABAARs are necessary for the reward enhancing effects and preference for oral benzodiazepines. Through a viral-mediated knockdown of α2GABAARs in the nucleus accumbens (NAc), we demonstrated that α2 in the NAc is necessary for the preference for midazolam. Findings imply that α2GABAARs in the NAc are involved in at least some reward-related properties of benzodiazepines, which might partially underlie repeated drug-taking behavior.Neuropsychopharmacology accepted article preview online, 19 February 2014; doi:10.1038/npp.2014.41.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2014; 39(8). DOI:10.1038/npp.2014.41 · 7.05 Impact Factor
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    • "BZ tolerance to the anticonvulsant action may develop with chronic exposure as a consequence of regulatory changes in the expression of GABA-A receptor subunits in specific brain areas. Tolerance develops quickly to the sedative and motor coordination effects of BZ anxiolytics, but not necessarily to the anxiolytic or memory impairing effects, and therapeutic drug doses are rarely increased with time (Licata and Rowlett 2008). Some patients develop tolerance to the hypnotic effects of BZs including the Z-drugs, as evidenced by rebound insomnia on withdrawal, and there are reports of abuse (Hajak et al. 2003). "
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    ABSTRACT: DefinitionBZs are used for a number of indications in general practice, neurology, anesthesiology, and psychiatry:InsomniaAdjuvants in anesthesiaAnxiety disorders (GAD, specific phobias, panic disorder, and social anxiety disorder)Adjustment disordersOrganic brain syndrome (acute, e.g., delirium tremens, and chronic, e.g., dementia)Anxiety in depression (as an adjunct at initiation of antidepressant therapy)Schizophrenia (catatonic type and for rapid tranquillization)Acute maniaAvoidant personality disorderAlcohol and sedative withdrawalSuicidal patients with prominent anxiety symptomsStatus epilepticusTardive dyskinesia and akathisiaSpasticity (e.g., spastic paraplegia) and acute torticollisContraindications: myasthenia gravis, sleep apnea, and severe pulmonary diseaseIntolerance of SSRIs/SNRIs is another important reason to prescribe benzodiazepines. SSRIs/SNRIs sometimes cause a paradoxical increase in anxiety at initiation of treatment that calls for adjunct prescribing of a BZ. Al ...
    Encyclopedia of Psychopharmacology, 01/2014: pages 1-8; , ISBN: 978-3-642-27772-6
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    • "Benzodiazepines (BZs) and related drugs such as zolpidem increase GABA-mediated inhibition via positive allosteric modulation of GABAA receptors throughout the central nervous system [1]. This drug class is commonly prescribed for treating anxiety, sleep, and seizure disorders, and while clinically valuable, their use can result in undesirable effects including memory impairment as well as abuse and dependence [2,3]. Given their widespread application, understanding more fully how BZs produce their effects is an important public health issue that will provide a framework for designing novel compounds to overcome their limitations as therapeutics. "
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    ABSTRACT: Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP), an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF) and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p.) injections of diazepam (10 mg/kg + 5 mg/kg) or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg), acute i.p. administration of both triazolam (0.03 mg/kg) and ZP (1.0 mg/kg) decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2) with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB) with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly.
    PLoS ONE 12/2013; 8(12):e84806. DOI:10.1371/journal.pone.0084806 · 3.23 Impact Factor
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